Fibroblast growth factor inhibits interferon gamma-STAT1 and interleukin 6-STAT3 signaling in chondrocytes.
Activation of fibroblast growth factor receptor 3 (FGFR3) leads to attenuation of cartilage growth. The members of the STAT family of transcription factors are believed to participate in FGFR3 signaling in cartilage, however the molecular mechanism of this action is poorly understood. Here, we demonstrate that a chronic FGF stimulus leads to accumulation of STAT1, 3, 5 and 6, evident in both in vitro chondrocyte model and murine limb explant cultures. Despite the accumulation, both endogenous and cytokine-induced activation of STAT1 and STAT3 is impaired by FGF, as demonstrated by imaging of active STAT nuclear translocation and analyses of STAT activatory phosphorylation and transcriptional activation. Further, we demonstrate that FGF induces expression of CIS, SOCS1 and SOCS3 inhibitors of gp130, a common receptor for the IL6-family of cytokines. Since cytokine-gp130 signaling represents an important positive regulator of cartilage, its inhibition may contribute to the growth-inhibitory effect of FGFR3 in cartilage.
Krejci
Pavel
P
Institute of Experimental Biology, Masaryk University, 61137 Brno, Czech Republic. krejcip@sci.muni.cz
Prochazkova
Jirina
J
Bryja
Vitezslav
V
Jelinkova
Petra
P
Pejchalova
Katerina
K
Kozubik
Alois
A
Thompson
Leslie Michels
LM
Wilcox
William R
WR
D000818:Animals; D001483:Base Sequence; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D051379:Mice; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D050822:Cytokine Receptor gp130; D016222:Fibroblast Growth Factor 2; D007371:Interferon-gamma; D015850:Interleukin-6; D051498:Receptor, Fibroblast Growth Factor, Type 3; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000093242:Interleukin-6 Inhibitors; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse